New potential HIV-1 inhibitors, analogues to efavirenz, containing the isatin core

HIV/AIDS remains a major global health challenge, with millions of new infections reported annually. Among the available antiretroviral therapies, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a crucial role by targeting viral reverse transcriptase (RT) through non-competitive inhibition. Efavirenz (EFV), a first-generation NNRTI, can serve as a lead compound in the development of new analogs due to its potent activity and well-characterized interaction with RT. In this study, a novel series of EFV analogs (10a-g) was designed using molecular hybridization strategies that combine EFV pharmacophores with a substituted isatin nucleus. The proposed compounds 10a-g were obtained in good yields through a synthetic route involving only two reaction steps. Compounds were evaluated for cytotoxicity, and anti-HIV activity was assessed in human T lymphocytic MT4 cells infected with HXB2 and TZM-bl cells infected with the NL4-3 strain. Compounds 10a, 10e, and 10g, exhibited inhibition of HIV replication in TZM-bl cells above 80%, with 10g demonstrating the most promising profile (98.72%). NERT assays confirmed RT inhibition, and molecular docking revealed binding modes and interaction energies consistent with experimental results. These findings support the ongoing development of EFV-based NNRTI analogs with improved antiretroviral properties.